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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2016)

One of the consequences of human aging is an overall decline in immune function. A hallmark of this aging process, termed immunosenescence, is the downregulation of co-receptor CD28 from the surface of CD8+ T cells. This population of terminally differentiated CD8+CD28– T cells accumulates during aging and chronic infections, and is linked to many age-related diseases observed in elderly individuals. In this thesis, we explore the molecular factors regulating CD8+CD28– T cell fate and function. In Chapter III, we find that resting CD8+CD28– T cells possess a unique glycolytic profile that is associated with their enhanced cytotoxicity and decreased expression of NAD+-dependent protein deacetylase SIRT1. Global gene–expression profiling identified the transcription factor FoxO1 as a SIRT1-target involved in the transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in CD8+CD28– T cells, and inhibiting its activity in CD8+CD28+ T cells recapitulates the metabolic and cytotoxic phenotype of resting CD8+CD28– T cells. In Chapter IV, we explore the signaling and functional consequences of IL-15, a pro-memory cytokine that serves as a TCR-independent activation signal for CD8+CD28– T cells. We find that IL-15 signals through mTOR to upregulate a metabolic program conducive for effector T cell function. Targeting CD8+CD28– T cells with a SIRT1 activator or glucose-starvation suppresses IL-15-induced cytotoxicity and proliferation. Altogether, this body of work identifies new molecular pathways that regulate the function of human CD8+CD28– T cells—providing deeper insight into the mechanisms of immune aging, as well as novel therapeutic opportunities to target it.

  • 1 supplemental file
Cover page: Elucidating Molecular Changes in CD8+ T cells During Aging
  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2015)
Over the past 15 years, protein acetylation has emerged as a globally important post-translational modification that fine-tunes major cellular processes in many life forms. This dynamic regulatory system is critical both for complex eukaryotic cells and for the viruses that infect them. HIV-1 accesses the host acetylation network by interacting with several key enzymes, thereby promoting infection at multiple steps during the viral life cycle. Inhibitors of host histone deacetylases and bromodomain-containing proteins are now being pursued as therapeutic strategies to enhance current antiretroviral treatment. As more acetylation-targeting compounds are reaching clinical trials, it is time to review the role of reversible protein acetylation in HIV-infected CD4(+) T cells.
    Cover page: Manipulation of the host protein acetylation network by human immunodeficiency virus type 1
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2017)
    Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T cell lines and in primary CD4+ T cells. SMYD2 associated with latent HIV-1 promoter chromatin, which was enriched in monomethylated lysine 20 at histone H4 (H4K20me1), a mark lost in cells lacking SMYD2. Further, we find that lethal 3 malignant brain tumor 1 (L3MBTL1), a reader protein with chromatin-compacting properties that recognizes H4K20me1, was recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. We propose that a SMYD2-H4K20me1-L3MBTL1 axis contributes to HIV-1 latency and can be targeted with small-molecule SMYD2 inhibitors.
      Cover page: SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2018)
      The expansion of CD8+CD28- T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28- T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28- T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28- T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28- T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28- T cells. These data identify the evolutionarily conserved SIRT1-FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.
        Cover page: Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1
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